The long-term objectives of this proposal are to develop and commercialize an effective therapeutic agent for malignant melanoma. The incidence of melanoma is on the increase. The current cumulative life-time risk for melanoma is 1:75 in the US, with approximately 20% developing metastatic disease. Metastatic malignant melanoma is resistant to current chemo- and immuno- therapy regimens. Median survival for patients with disseminated disease ranges 4-15 months. Clearly there is a need for a new and efficacious melanoma treatments. A novel rhenium (Re) cyclized alpha-melanocyte stimulating hormone analog that targets melanoma has been developed in our laboratory. The peptide [DOTA]- ReCCMSH was designed to be radiolabeled with Alpha-particle emitting radionuclides. Alpha-particle radiation is highly focused and very potent. Only a few Alpha-particle emitting radionulcides are necessary to cause cell death. Radiolabeled [DOTA] ReCCMSH has low nanomolar affinity for the melanocortin-1 receptor present on melanoma tumor cells and is rapidly internalized upon binding. In vivo biodistrubution studies have shown that radiolabeled [DOTA]- ReCCMSH displays high tumor uptake and extended tumor retention properties coupled with rapid clearance kinetics. It is hypothesized that melanoma specific deposition of Alpha-particle emitting radionuclides by [DOTA]-ReCCMSH will result in tumor cell death. The specific aims of this Phase-ll STTR proposal are to scale up production of high specific activity [DOTA]-ReCCMSH and determine its maximum tolerated dose and therapeutic efficacy in human and mouse melanom animal modes. In addition, acute toxicity studies will be performed in mouse and swine with the non-radiolabeled [DOTA]-ReCCMSH to demonstrate that the peptide-targeting vehicle is non-toxic. The results of these studies will be used to support an investigational new drug application to the Food and Drug Administration for phase-l clinical trials. [DOTA]-ReCCMSH targeting of Alpha-particle emitting radiation to melanoma tumors in patients with metastatic disease.